Topical therapy for migraine

ABSTRACT

The invention is directed to formulations and methods of treating a migraine and/or cluster headache with a serotonin agonist, pharmaceutically acceptable salt thereof, or derivative thereof.

Applicant hereby claims priority of U.S. patent application Ser. No.11/999,093 filed Dec. 3, 2007; U.S. patent application Ser. No.10/163,234, filed on Jun. 5, 2002, which claims the benefit of U.S.Provisional Patent Application No. 60/296,286, filed Jun. 5, 2001, thedisclosures of which are incorporated herein by reference in theirentireties for all purposes.

BACKGROUND OF THE INVENTION

Migraine headaches are a debilitating condition in which some 53 millionpersons per year suffer acute pain. Frequently, migraine is accompaniedby sickness and vomiting and a sensitivity to light and noise.

Since the discovery of serotonin (5-hydroxytryptamine, 5-HT) over fourdecades ago, the cumulative results of many diverse studies haveindicated that serotonin plays a significant role in the functioning ofthe mammalian body, both in the central nervous system and in peripheralsystems as well. Morphological studies of the central nervous systemhave shown that serotonergic neurons, which originate in the brain stem,form a very diffuse system that projects to most areas of the brain andspinal cord. R. A. O'Brien, Serotonin in Mental Abnormalities, 1: 41(1978); H. W. M. Steinbusch, HANDBOOK OF CHEMICAL NEUROANATOMY, Volume3, Part 11, 68 (1984); N. E. Anden, et al., Acta PhysiologicaScandinavia, 67: 313 (1966). These studies have been complemented bybiochemical evidence that indicates large concentrations of 5-HT existin the brain and spinal cord. H. W. M. Steinbusch, supra.

Serotonin (5-hydroxytryptamine, 5-HT) is said to play a key role inregulating the vascular tone, and serotonin deficiency is said to resultin a vasodilatation causing the migrainous headache. The onset of actionis effected via 5-HT₁-receptors in the region of the vascular walls ofcerebral arteries.

Accordingly, in the last few years, the chemical structure of serotoninhas been modified in various manners, resulting in changes of thepharmacological properties. For example, indole derivatives weresynthesized which cause the cerebral vessels to be selectively tonizised(contracted) combined with a rapid improvement of the symptoms. Theseare so-called serotonin agonists having a particular affinity for5-HT₁-receptors.

The class of serotonin agonists having a particular affinity for 5-HT₁receptors is typified, for example, by sumatriptan, zolmitriptan,naratriptan, and rizatriptan to name a few. Oral bioavailability is animportant factor in the efficacy of a drug and one that may account forconsistency of response with repeated use. Sumatriptan tablets have alow oral bioavailability (14%). All of the second-generation triptanshave improved bioavailability (rizatriptan and zolmitriptan, 40-45%;naratriptan, close to 70%). Sumatriptan, rizatriptan, and zolmitriptanare metabolized by the MAO system. All of these compounds, however, havesome adverse effects which require supervised administration atefficacious doses. PHYSICIAN'S DESK REFERENCE, (48th ed., 1994).

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a method for thetreatment of migraines in humans via the topical administration of aserotonin agonist.

It is an object of certain embodiments of the present invention toprovide a topical therapeutic formulation for the systemic and/orregional administration of a compound having serotonin agonist activity.

It is an object of certain embodiments of the present invention toprovide a topical therapeutic formulation and method for the regionaladministration of a compound having serotonin agonist activity.

It is an object of certain embodiments of the present invention toprovide a more rapid therapeutic effect than previous routes ofadministration of serotonin agonist.

The above objects and others are attained by virtue of the presentinvention, which is directed in part to a method of treating a migraineand/or cluster headache via the topical administration and delivery of atherapeutically effective amount of a serotonin agonist to a human inneed of treatment thereof.

In certain embodiments, the present invention is directed to a method oftreating a migraine and/or cluster headache comprising applying aserotonin agonist to the headache region of a human patient in aneffective amount to provide relief of a migraine and/or cluster headachewhich is occurring or imminent in the human patient.

In certain embodiments, the present invention is directed to a unit doseof a serotonin agonist for topical administration and delivery of theserotonin agonist to a human in need of treatment thereof.

In certain preferred embodiments, the serotonin agonist is in a topicalformulation. In certain other preferred embodiments, the serotoninagonist is in a transdermal therapeutic system. Preferably the topicalformulation or transdermal therapeutic system is applied to apredetermined area of skin to deliver the serotonin agonist to a human.

In certain preferred embodiments, the formulations of the presentinvention provide an effective dose of the serotonin agonist at theapplication site, which is quickly absorbed. Most preferably theformulations of the present invention are immediate releasingformulations, such that a therapeutically effective amount of theserotonin agonist is available for rapid absorption. The formulations ofthe present invention preferably are suitable for the treatment of anacute migraine attack.

The topical formulation comprising the serotonin agonist or transdermaltherapeutic system comprising the serotonin agonist is preferablyapplied to the posterior cervical region of the human experiencing orabout to experience a migraine and/or cluster headache. Most preferably,the topical formulation or transdermal therapeutic system is applied tothe back of the neck, preferably in close proximity to or on the area ofskin above the brain stem.

In certain preferred embodiments the symptoms of the migraine or clusterheadache are relieved within about 2 hours, preferably within about 5minutes to about 2 hours, within about 5 minutes to about I hour andmost preferably within about 5 minutes to about 30 minutes afterapplication of the serotonin agonist. In certain preferred embodiments,the formulations of the present invention provide migraine or clusterheadache relief within from less than 1 minute to about 2 hours, about 1minute to about 2 hours, preferably in about 1 minute to about 15minutes.

In certain embodiments, the present invention is directed towards a unitdose of a topical formulation for treating a migraine or clusterheadache comprising a serotonin agonist incorporated into apharmaceutically acceptable vehicle for topical administration onto theskin of a human patient; said unit dose providing said serotonin agonistin a form which is immediately absorbable when said unit dose is appliedonto human skin; said serotonin agonist comprising from about 0.5 toabout 200 mg of sumatriptan, by weight based on the succinate salt, or atherapeutic equivalent dose of another topically absorbablepharmaceutically acceptable serotonin agonist; and said unit doseproviding relief from a migraine or cluster headache within about 2hours after topical administration to said human patient.

In certain embodiments, the present invention is directed to a unit doseof a topical formulation for treating a migraine or cluster headachecomprising a serotonin agonist; and a pharmaceutically acceptablevehicle; said unit dose containing from about 0.5 mg to about 200 mg ofsaid serotonin agonist, and providing pain relief in at least 50 percentof a population of patients experiencing a migraine or cluster headache,in a time period within about 2 hours after application of the unit doseto the headache region.

In certain embodiments, the present invention is further directed to amethod of reducing side effects of a serotonin agonist administered inmigraine or cluster headache therapy comprising topically administeringa therapeutically effective amount of a serotonin agonist to theheadache region of a patient in need of migraine or cluster headachetherapy.

In certain embodiments of the present invention, the formulationcomprising the serotonin agonist, further comprises one or moreingredients selected from the group consisting of ethoxydiglycol, water,glycerine, C₁₂₋₁₅alkyl benzoate, glyceryl stearate, dimethicone,cetearyl alcohol, cetearyl glucoside, polyacrylamide, cetyl alcohol,magnesium aluminum silicate, xanthan gum, aloe vera (aloe barbadensis),tocopheryl acetate (vitamin E acetate), prunus amygadalus amara (bitteralmond) kernel oil, vitis vinifera (grape) seed extract, triticumvulgare (wheat) germ oil, retinyl palmitate (vitamin A palmitate),ascorbyl palmitate (vitamin C palmitate), pro-lipo multi-emulsionliposomic system, tetrasodium EDTA, phenoxyethanol, and sodiumhydroxymethylglycinate.

In certain embodiments, the methods of the present invention furtherinclude applying an additional dose of a serotonin agonist to theheadache region about 15 minutes to about 3 hours after the firstapplication of a serotonin agonist, preferably 30 minutes to about 2hours after the first application of a serotonin agonist, and mostpreferably from about 30 minutes to about 1 hour after the firstapplication of a serotonin agonist. This embodiment is consideredparticularly useful when the first application does not alleviate thesymptoms of the migraine.

In certain preferred embodiments, the formulations of the presentinvention are provided in a metered dose device. Preferably the metereddose device provides multiple unit doses of the topical preparation.Certain metered dose devices include, for example and withoutlimitation, a syringe without a needle (e.g., a tuberculin syringewithout needle, a dropper, a metered dose spray device, metered tube,and the like. Preferably the metered dose device includes an actuatorcapable of being actuated to dispense single unit doses comprising theserotonin agonist from the device.

In certain embodiments, the present invention is further directedtowards a method of manufacturing the formulations described herein.

For purposes of the present invention, a “topical formulation” includes,for example, ointments, creams, lotions, pastes, gels, foams, viscousliquids, semisolids, etc., which releases one or more drugs at apredetermined rate over a defined period of time to a defined site ofapplication.

For purposes of the present invention, a “transdermal therapeuticsystem” is defined as a drug-containing device (including e.g., patch,disc, etc.) which releases one or more drugs at a predetermined rateover a defined period of time to a defined site of application.

For purposes of the present invention, “transdermal” delivery is thedelivery by passage of a drug through the skin and into the bloodstream.

For purposes of the present invention the term “immediate release” meansthat the serotonin agonist is available for immediate absorption (e.g.,available within 0 to about 5 minutes) upon application of theformulation. This is in contrast to a delayed or prolonged absorptionwhich typically results from, e.g., a transdermal therapeutic device).

For purposes of the present invention “therapeutically effective” or“effective” amount is meant to be a nontoxic but sufficient amount of acompound to provide the desired therapeutic effect, e.g., avoidance ofthe onset of a migraine and or increased alleviation of the migraineand/or cluster headache. In the present case, for example, it is thedose of serotonin agonist which will be effective in relieving symptomsof the migraine or cluster headache. An “effective” amount of apermeation enhancer as used herein, for example, means an amount thatwill provide the desired increase in skin permeability and,correspondingly, the desired depth of penetration, rate ofadministration, and amount of drug to be delivered.

For purposes of the present invention, the term “delivers” when usedwith respect to the topical formulation or transdermal therapeuticsystem means that the formulation or system provides a mean relativerelease rate or flux of the drug out of the formulation or system andthrough the skin of the patient.

By “predetermined area of skin” is intended a defined area of intactunbroken living skin. In certain embodiments of the present invention,the predetermined area will be in the range of about 1 cm² to about 100cm², preferably in the range of about 10 cm² to about 100 cm², morepreferably in the range of about 20 cm² to about 60 cm². However, itwill be appreciated by those skilled in the art of topical delivery thatthe area of skin through which drug is administered may varysignificantly, depending on the formulation, dose, the application ofthe formulation, and the like.

“Penetration enhancement” or “permeation enhancement” for purposes ofthe present invention relates to an increase in the permeability of skinto a pharmacologically active agent, i.e., so as to increase the rate atwhich the drug permeates through the skin and enters the bloodstream.The enhanced permeation effected through the use of such enhancers canbe observed by measuring the rate of diffusion of drug through animal orhuman skin using a diffusion cell apparatus.

For purposes of the present invention, the “headache region” is definedas the skin region of the head and/or neck above which a patient feels amigraine or cluster headache pain is occurring or is imminent. Typicallythe headache region includes, for example, the frontotemporal regionand/or upper posterior cervical area on the side of the headache.Preferably the headache region includes the posterior cervical area inclose proximity to the brain stem. Preferably this area is a relativelyhairless area of the patient's head and/or neck.

DETAILED DESCRIPTION

Sickness and vomiting typically occurring in migraine make an oralapplication of the active substance for migraine treatment difficult.Therefore, the administration by the topical administration of aserotonin agonist may offer considerable advantages.

Certain other advantages of topical administration may include increasedefficiency by avoiding the first-pass effect of the liver, avoidingdiscomfort and risks of an intravenous treatment, avoiding side effectsin the region of the gastrointestinal tract in the case of oralmedication, and good patient acceptance. Absorption peaks involving therisk of systemic side effects may also be avoided.

In the prior art, there have been previous attempts to provide for amore efficacious and safe treatment using serotonin agonists specificfor the treatment of 5-HT₁ receptor subtype.

For Example, U.S. Pat. No. 5,863,935 to Robertson et al. describescertain compounds having “5-HT₁-like” receptor agonist properties andtheir administration in a number of ways, including topical orintranasal application.

Additionally, U.S. Pat. No. 5,805,571 to List, describes a transdermaltherapeutic system for the systemic administration of active substanceswherein at least one of the active substances listed is a serotoninagonist of the group comprising indole derivatives. Typically,transdermal systems are not used in acute situations because they do notprovide an immediate effect, but rather provide prophylaxis or prolongedeffect. Transdermal systems such as that described in the '571 patent toList require a period of time for the drug to pass through a barrierlayer and onto/into the skin which may take e.g., a substantial periodof time until the dose of drug that is absorbed is sufficient toalleviate the pain associated with the headache.

The above-mentioned patents do not suggest the application of thetopical formulation or transdermal therapeutic system on the skin abovethe site of the migraine or cluster headache attack. Typically the siteof administration of transdermal delivery systems have been selected atvarious locations such as on the chest, on the arm, on the genitalia, oron the thigh for various reasons such as desired skin permeability to anagent, convenience or cosmetic reasons. According to the presentinvention the topical formulation is preferably applied to the headacheregion for the local (e.g., regional) and systemic administration ofagents to the migraine or cluster headache area and in certainembodiments results in lower serum levels necessary to provide atherapeutic effect than that reported in the prior art.

This method and the formulations described herein allow for the headacheto be treated much faster and more effectively than such prior art modesof administration. For example, it is contemplated that a patientexperiencing a migraine or cluster headache, or who perceives that sucha headache is imminent, can apply the dose of serotonin agonist to theskin at that site and experience relief within, e.g., from about 2hours, preferably within about 5 minutes to about 2 hours, within about5 minutes to about 1 hour, about 5 minutes to about 30 minutes. In amost preferred embodiments, relief is experienced within from less than1 minute to about 2 hours, from less than 1 minute to about 30 minutes,or from less than 1 minute to about 15 minutes after application of theserotonin agonist. The method of the invention further contemplates thatif the dose does not completely alleviate the headache, that a seconddose may be applied within about 3 hours, preferably within about 15minutes to about 3 hours, within about 30 minutes to about 2 hours, andmost preferably within about 30 minutes to about 1 hour after the firstapplication.

By the methods of the present invention, a substantial percentage ofpatients experience relief within a relatively short period of timeafter application. For example, as demonstrated in at least one studydescribed herein, more than 50 percent of the patients experienced painrelief within one hour of the application of the dose of serotoninagonist to the headache region. In certain preferred embodiments, morethan 70 percent, most preferably more than 80 percent, of the patientsexperienced pain relief.

In certain embodiments of the present invention, the method of treatinga human patient suffering from migraine or cluster headache comprisesapplying a topical formulation which comprises a serotonin agonist, asdescribed herein, to the headache region, such that the topicalformulation delivers an amount of serotonin agonist which istherapeutically effective. Preferably the topical formulation contains aunit dose of the serotonin agonist that provides relief of a migraineand/or cluster headache. In certain embodiments, the present inventionprovides a method of treating an imminent migraine attack in a patientcomprising topically administering a serotonin agonist to the patient inneed of such treatment.

The methods of the present invention may also, if desired, involvepre-treatment of the skin with an enhancer to increase the permeabilityof the skin to the applied drug. The methods of the present inventionmay include pre-treatment or “prepping” of the skin area with asubstance that opens up the skin pores. Additionally, the methods of thepresent invention may include, if desired, pre-treatment or “prepping”of the skin with an alcohol swab or the like to rid the area of dirt,make-up, oil, and the like, prior to application of the drug.

In certain embodiments, the topical formulation of the present inventioncomprises a serotonin agonist in an amount which is therapeuticallyeffective when administered topically at the headache region, but whichprovides a plasma concentration which is subtherapeutic if orallyadministered.

In certain embodiments, by applying the formulation of the presentinvention comprising a dose of serotonin agonist at the headache regionof the migraine or cluster headache, it may be possible for the use oflower doses of drug or faster relief of the headache than if applied tothe trunk or limbs of a human patient, and the lower plasma levels ofdrug which result from lower doses may thereby reduce unwanted sideeffects of the serotonin agonist. For purposes of the present invention,the “trunk” of a human is the body of a human excluding the head, neckand limbs.

The serotonin agonist for use in the present invention, includes forexample and without limitation, sumatriptan, naratriptan, eletriptan,rizatriptan, zolmitriptan, almotriptan, frovatriptan, pharmaceuticallyacceptable salts thereof, mixtures thereof, and derivatives thereof.Preferably the serotonin agonist is sumatriptan(3-(2-(dimethylamino)ethyl)-N-methyl-1H-indole-5-methanesulfonamide),one of its salts or derivatives. As used herein, the identification ofan agent to be delivered includes not only the serotonin agonist per sebut also its topically administrable prodrugs, active metabolites andprodrugs of the active metabolites.

Every triptan has a basic indole ring, but their side chains differ.These side chains affect the pharmacokinetics of these agents in waysthat may be clinically significant and which may make them more or lesseffective transdermally.

Sumatriptan, the first available drug in this class of triptans, is ashort-acting triptan with a rapid onset. It is available in three dosageforms; in the order of decreasing speed of onset of action, these are:subcutaneous injection, nasal spray, and oral tablet. The second triptanon the market was zolmitriptan, which has better bioavailability thansumatriptan, but is otherwise quite similar in clinical use.Zolmitriptan is available in an oral tablet formulation. Zolmitriptan,unlike sumatriptan does cross an intact blood-brain barrier, but theclinical relevance of this is unclear. The third available triptan wasrizatriptan which has a rapid onset of action and is available in aconventional oral tablet formulation and also in a rapid-dissolving discformulation, called MLT. MLT disc rapidly dissolves in the mouth withoutwater. The fourth available triptan was naratriptan, which isdistinctive in having a slower onset of action and a longer half-lifethan other triptans.

Comparative oral doses of certain triptans are as follows: sumatriptan,50 mg; rizatriptan, 10 mg; naratriptan, 2.5 mg; zolmitriptan, 2.5 mg;and eletriptan, 40 to 80 mg. Therefore, one skilled in the art canreadily determine therapeutically equivalent doses of serotonin agoniststhat may be useful in the present invention. However, it is noted thatthe differences in oral doses may not directly correspond to thedifferences in doses that are therapeutically effective via transdermaldelivery of the serotonin agonist. Factors such as metabolism of theserotonin agonist, the ability of the drug to pass through the skin,among others, may affect the amount of serotonin agonist necessary toprovide a therapeutic effect. One skilled in the art would readilyunderstand this and adjust for the same.

The synthesis of certain serotonin agonists of the present invention canbe carried out according to British Patents No. 2 124 210 B and 2 162522 B; EP-0 500 086 A; EP-A-303 507; U.S. Pat. No. 4,997,841; EP-A-592438; U.S. Pat. No. 5,545,644; WO 9206973; EP-A-486 666; EP-A-636 623;U.S. Pat. No. 5,399,574; 5,466,699; WO 91/18897, the disclosures ofwhich are hereby incorporated by reference.

In certain preferred embodiments, the methods of the present inventionfurther include a method of treating a human patient suffering frommigraine or cluster headache comprising applying a topical formulation,or transdermal therapeutic system, comprising sumatriptan, apharmaceutically acceptable salt thereof, or derivative thereof, to theheadache region of the patient, the topical formulation providing aserum level of sumatriptan from about 5 ng/ml to about 110 ng/ml,preferably from about 10 ng/ml to about 80 ng/ml. In certainembodiments, the method provides a serum level of sumatriptan from about50 ng/ml to about 70 ng/ml.

In certain embodiments of the present invention, the serotonin agonistis in an amount of from about 0.5 mg to about 200 mg, preferably theserotonin agonist is in an amount of from about 0.5 mg to about 100 mg,and most preferably from about 10 mg to about 100 mg.

In certain preferred embodiments, the formulations of the presentinvention contain sumatriptan base or a pharmaceutically acceptable saltthereof (e.g., sumatriptan succinate) as the serotonin agonist. When theserotonin agonist is sumatriptan or a pharmaceutically acceptable saltthereof, the amount of sumatriptan is in an amount of from about 0.5 mgto about 200 mg, preferably in an amount of from about 5 mg to about 200mg, from about 5 mg to about 100 mg, from about 5 mg to about 50 mg, orfrom about 5 mg to about 25 mg, and most preferably is in an amount of12.5 mg, 25 mg, 50 mg or 100 mg.

The amount that constitutes a therapeutically effective amount may varyaccording to any drugs being coadministered with the serotonin agonist,desired duration of treatment, the surface area of the skin over whichthe formulation or device is to be placed, and other components of theformulation or device. Accordingly it is not practical to enumerateparticular preferred amounts but such can be readily determined by thoseskilled in the art with due consideration of these factors. Generally,however, when the serotonin agonist is present in a device of theinvention, the serotonin agonist is present in an amount by weight ofabout 1 to about 25 percent, preferably about 5 to 15 percent, by weightbased on the total weight of the adhesive layer.

In certain embodiments of the present invention, the serotonin agonistis in a topical administration form (e.g., a topical formulation) of anointment, cream, lotion, paste, gel, or the like.

A topical formulation containing a serotonin-agonist in accordance withthis invention may be used to treat any condition capable of treatmentwith serotonin agonists, e.g., migraine headaches and cluster headaches.The topical formulation can be placed on the skin of the headache regionand allowed to remain for a time sufficient to achieve or maintain theintended therapeutic effect.

The topical formulations of the present invention (e.g., ointment, gel,cream, or the like), must be suitable for topical administration of adrug, i.e., must contain pharmaceutically acceptable excipientscompatible with application to the skin tissue, and may optionallycontain a sufficient amount of an enhancer composition as describedhereinafter.

In certain embodiments, in addition to the serotonin agonist, thetopical formulations and/or transdermal therapeutic systems of thepresent invention may include at least one adjuvant such as apenetration enhancer, anti-oxidant, stabilizer, carrier, or vehicle.Additionally or alternatively, the present invention may include theapplication of electric current (iontophoresis) for enhancing permeationof the serotonin agonist.

In certain embodiments of the present invention, wherein the topicalformulation further includes a penetration enhancer composition, theamount of enhancer composition present in the formulation will depend ona number of factors, e.g., the strength of the particular enhancercomposition, the desired increase in skin permeability, and the amountof drug which is necessary to deliver.

In certain embodiments, the topical formulations comprising a serotoninagonist in an ointment, gel, cream or the like, will typically containon the order of about 0.001 to about 80% by weight, preferably 0.01 wt.% to 50 wt. % serotonin agonist, and about 0 wt. % to about 50.0 wt. %,preferably from about 1 wt. % to about 30 wt. % of a permeation enhancercomposition, with the remainder of the composition comprising a carrieror vehicle.

Suitable enhancers include, but are not limited to, dimethylsulfoxide(DMSO), N,N-dimethylacetamide (DMA), decylmethylsulfoxide (C₁₀ MSO),polyethylene glycol monolaurate (PEGML), propylene glycol (PG), PGML,glycerol monolaurate (GML), lecithin, the 1-substitutedazacycloheptan-2-ones, particularly 1-n-dodecylcyclazacycloheptan-2-one(available under the trademark Azone® from Whitby Research Incorporated,Richmond, Va.), alcohols, and the like. The permeation enhancer may alsobe a vegetable oil as described in U.S. Pat. No. 5,229,130 to Sharma.Such oils include, for example, safflower oil, cotton seed oil and cornoil.

Additional enhancers for use in conjunction with the present inventionare lipophilic compounds having the formula [RCOO]_(n)R′, wherein n is 1or 2 and R is C₁-C₁₆ alkyl optionally substituted with 1 or 2 hydroxylgroups, and R′ is hydrogen or C₁-C₁₆ alkyl optionally substituted with 1or 2 hydroxyl groups. Within this group, a first subset of compounds arerepresented by the formula [CH₃(CH₂)_(m)COO]_(n)R′ in which m is aninteger in the range of 8 to 16, n is 1 or 2, and R′ is a lower alkyl(C₁-C₃) residue that is either unsubstituted or substituted with one ortwo hydroxyl groups. Preferred enhancers within this group include anester which is a lower alkyl (C₁-C₃) laurate (i.e., m is 10 and n is 1)such as “PGML”. It will be appreciated by those skilled in the art thatthe commercially available material sold as “PGML” is typically althoughnot necessarily a mixture of propylene glycol monolaurate itself,propylene glycol dilaurate, and either propylene glycol, methyl laurate,or both. Thus, the terms “PGML” or “propylene glycol monolaurate” asused herein are intended to encompass both the pure compound as well asthe mixture that is typically obtained commercially. Also within thisgroup is a second subset of compounds, namely, esters of fatty alcoholsrepresented by the formula CH₃ (CH₂)_(m)—O—CO—CHR₁R₂, in which R₁ and R₂are independently hydrogen, hydroxyl, or lower alkyl (C₁-C₃), and m isas above. Particularly preferred enhancers within this group are lauryllactate and myristyl lactate. In addition, a third subset of compoundswithin this group are analogous fatty acids, i.e., acids having thestructural formula CH₃(CH₂)_(m)COOH where m is as above. A particularlypreferred acid is lauric acid.

Other enhancer compositions are wherein a lipophilic compound as justdescribed, particularly PGML is combined with a hydrophilic compound,such as a C₂-C₆ alkanediol. One preferred hydrophilic enhancer withinthis group is 1,3-butanediol. Such enhancer compositions are describedin detail in PCT Publication No. WO 95/05137, published Feb. 23, 1995,herein incorporated by reference. Another hydrophilic enhancer that maybe included in these compositions is an ether selected from the groupconsisting of diethylene glycol monoethyl ether (Transcutol®) anddiethylene glycol monomethyl ether. Such enhancer compositions aredescribed in detail in U.S. Pat. Nos. 5,053,227 and 5,059,426 to Chianget al., the disclosures of which are herein incorporated by reference.

Other enhancer compositions may include mixture or combinations of anyof the aforementioned enhancers, and the like.

In certain embodiments the topical formulation may include at least onewater-insoluble, pharmacologically approved, alkyl cellulose orhydroxyalkyl cellulose, and the like. Alkyl cellulose or hydroxyalkylcellulose polymers for use in this invention include ethyl cellulose,propyl cellulose, butyl cellulose, cellulose acetate, hydroxypropylcellulose, hydroxybutyl cellulose, and ethylhydroxyethyl cellulose,alone or in combination. In addition, a plasticizer or a cross linkingagent may be used to modify the polymer's characteristics. For example,esters such as dibutyl or diethyl phthalate, amides such asdiethyldiphenyl urea, vegetable oils, fatty acids and alcohols such asacid oleic and myristyl may be used in combination with the cellulosederivative.

In certain embodiments, the topical formulation may further includehydrocarbons such as liquid paraffin, vaseline, solid paraffin,microcrystalline wax, etc.; higher aliphatic alcohols such as cetylalcohol, hexadecyl, alcohol, stearyl alcohol, oleyl alcohol, etc.;esters of higher fatty acids with higher alcohols such as beeswax, etc.;esters of higher fatty acids with lower alcohols such as isopropylmyristate, isopropyl palmitate, etc.; vegetable oils, modified vegetableoils, hydrous lanolin and its derivative, squalene, squalane; higherfatty acids such as palmitic acid, stearic acid, etc. and the like.

In certain embodiments, the topical formulation may further includeemulsifiers and dispersing agents which include, for example, anionic,cationic and nonionic surfactants. Nonionic surfactants are preferredbecause of their low levels of irritation to skin. Typical of nonionicsurfactants are fatty acid monoglycerides such as glyceryl monostearate,etc.; sorbitan fatty acid esters such as sorbitan monolaurate, etc.;sucrose fatty acid esters; polyoxyethylene fatty acid esters such aspolyoxyethylene stearate, etc.; and polyoxyethylene higher alcoholethers such as polyoxyethylene cetyl ether, polyoxyethylene oleyl ether,etc.

In certain embodiments of the present invention, the topical formulationmay include a gelling agent such as methylcellulose, ethylcellulose,hydroxyethylcellulose, hydroxypropyl-cellulose,hydroxypropylmethylcellulose, carboxymethylcellulose, carbomer, and thelike.

In certain embodiments of the present invention, it has been found thatthe percentage of patients experiencing migraine or cluster headachepain relief may be significantly improved based on an aqueous basedtopical formulation as demonstrated by the appended examples. Someexamples of patents disclosing pharmaceutical compositions which relyupon an aqueous gel composition as a vehicle for the application of adrug are U.S. Pat. Nos. 4,883,660; 4,767,619; 4,511,563; 4,861,760; and5,318,780, the disclosures of which are herein incorporated byreference.

The topical formulation may further include one or more preservatives,stabilizers, or anti-oxidants.

Examples of preservatives that may be used in a formulation according tothe present invention include, but are not limited to, bacteriostaticcompounds and other preservatives suitable for topical administrationincluding various alcohols, sorbic acid and salts and derivativesthereof, ethylenediamine, monothioglycerol, and thimerosal.

Examples of stabilizers that may be present in a formulation accordingto the present invention include pH buffers suitable for topicaladministration, complexing agents, chelating agents and the like.

Examples of anti-oxidants that may be used in a formulation according tothe present invention include ascorbic acid and its derivatives, e.g.,ascorbyl palmitate, as well as butylated hydroxyanisole, butylatedhydroxytoluene, sodium bisulfite, sodium metabisulfite, and others.

Other adjuvants that may be included in the drug formulation includecarriers, tackifiers, pigments, dyes, and other additives that do notadversely affect the mechanical or adhesive properties of theformulation.

“Carriers” or “vehicles” as used herein refer to carrier materialssuitable for transdermal drug administration, and include any suchmaterials known in the art, e.g., any liquid, gel, emulsion, solvent,liquid diluent, solubilizer, or the like, which is nontoxic and whichdoes not interact with other components of the composition in adeleterious manner. The term “carrier” or “vehicle” as used herein mayalso refer to stabilizers, crystallization inhibitors, dispersing agentsor other types of additives useful for facilitating transdermal drugdelivery. It will be appreciated that compounds classified as “vehicles”or “carriers” may sometimes act as permeation enhancers, and vice versa,and, accordingly, these two classes of chemical compounds orcompositions may sometimes overlap.

Carrier materials suitable for use in the instant compositions includethose well-known for use in the cosmetic and medical arts as bases forointments, lotions, salves, aerosols, suppositories and the like.Suitable carriers include, for example, water, liquid alcohols, liquidglycols, liquid polyalkylene glycols, liquid esters, liquid amides,liquid protein hydrolysates, liquid alkylated protein hydrolysates,liquid lanolin and lanolin derivatives, and like materials commonlyemployed in cosmetic and medicinal compositions. Other suitable carriersherein include for example alcohols, including both monohydric andpolyhydric alcohols, e.g., ethanol, isopropanol, glycerol, sorbitol,2-methoxyethanol, diethyleneglycol, ethylene glycol, hexyleneglycol,mannitol, and propylene glycol; ethers such as diethyl or dipropylether; polyethylene glycols and methoxypolyoxyethylenes (carbowaxeshaving molecular weight ranging from 200 to 20,000); polyoxyethyleneglycerols, polyoxyethylene sorbitols, stearoyl diacetin, and the like.

In certain embodiments of the present invention, the formulations of thepresent invention may be formulated as a transdermal delivery system(also referred to herein as a transdermal therapeutic system) such as atransdermal patch, a transdermal plaster, a transdermal disc,iontophoretic transdermal device, or the like.

In certain embodiments, the serotonin-agonist containing transdermaldelivery devices, as well as other transdermal delivery systems inaccordance with the invention can be made in the form of an article suchas a tape, a patch, a sheet, a dressing or any other form known to thoseskilled in the art. Generally the device will be in the form of a patchof a size suitable to deliver a unit dose of serotonin agonist throughthe skin. The serotonin agonist may be introduced into a transdermaltherapeutic system in different forms (solid, in solution, indispersion); it may also be microencapsulated.

In certain embodiments the present invention provides a transdermaltherapeutic system comprising a serotonin agonist in an amount thatwould provide sub-therapeutic plasma levels if administered orally, butis therapeutically effective when administered via transdermal deliveryat the headache region.

A transdermal delivery system for use in accordance with the presentinvention can also be constructed with an enhancer composition and otheringredients described hereinabove with respect to the topicalformulation. Preferably the transdermal delivery system is formulatedfor the rapid delivery of a serotonin agonist as would be beneficial toa person suffering from a migraine or a cluster headache. The targetedskin flux for delivery of a particular drug can be achieved by adjustingvehicle composition and vehicle loading, as well as by adjusting thesurface area through which the compositions are administered to skin.

The transdermal delivery system used in the present invention may beprepared, for example, in accordance with U.S. Pat. Nos. 5,069,909;4,806,341; 5,026,556; 4,588,580; 5,016,652; 3,598,122; 4,144,317;4,201,211; 4,262,003; and 4,379,454; all of which are incorporatedherein by reference.

In certain embodiments of the present invention, wherein the transdermaldelivery system is a transdermal patch, the transdermal patch comprisesa serotonin agonist contained in a reservoir or a matrix, and anadhesive which allows the transdermal patch to adhere to the skin,allowing the passage of the active agent from the transdermal patchthrough the skin of the patient. Once the serotonin agonist haspenetrated the skin layer, the drug is absorbed into the blood streamwhere it exerts the desired pharmaceutical effects.

In certain embodiments, the dosage form can be a transdermal patchcomprising a laminated composite for administering said serotoninagonist to an individual transdermally comprising: (a) a polymer backinglayer that is substantially impermeable to said serotonin agonist; and(b) a reservoir layer comprising a water-base acrylatepressure-sensitive adhesive, 1 to 12% by weight serotonin agonist and 2to 25% by weight of a permeation enhancer comprising propylene glycolmonolaurate in combination with capric acid or oleic acid, wherein theskin contact area of the composite is 10 to 100 cm².

The dosage form can be a transdermal patch comprising (a) a polarsolvent material selected from the group consisting of C₃-C₄ diols,C₃-C₆ triols, and mixtures thereof; and (b) a polar lipid materialselected from the group consisting of fatty alcohol esters, fatty acidesters, and mixtures thereof; wherein said polar solvent material andsaid polar lipid material are present in a weight ratio of solventmaterial:lipid material of from about 60:40 to about 99:1.

In certain embodiments, the dosage form also comprises a transdermalplaster comprising: a film layer which comprises a polyester film of 0.5to 4.9 μm thickness, 8 to 85 g/mm strength, respectively in the twodirections intersecting substantially at right angles, 30 to 150%elongation, in the two directions intersecting substantially at rightangles and an elongation ratio of A to B of 1.0 to 5.0, wherein A and Brepresent data in two directions intersecting at right angles, and A isgreater than B, and wherein said polyester film comprises 0.01 to 1.0%by weight, based on the total weight of said polyester film, of solidfine particles in which (a) the average particle size is 0.001 to 3.0μm, and (b) the average particle size is substantially not more than 1.5times the thickness of said polyester film; and an adhesive layer (a)which is composed of an adhesive containing said serotonin agonist andfurther wherein said adhesive layer (a) is laminated on said film layerover the surface in a 2 to 60 μm thickness.

In certain embodiments, the dosage form can be a transdermal disccomprising: (a) a backing layer which is substantially impervious tosaid serotonin agonist; and (b) a polymer matrix disc layer which isadhered to said backing layer and which has microdispersed therein saidserotonin agonist, said polymer being bioacceptable and permitting saidserotonin agonist to be transmitted for transdermal absorption, saidserotonin agonist being stable in said polymer matrix.

In certain preferred embodiments, the treatment of the migraine and/orcluster headache is by application of the transdermal therapeutic system(e.g., patch) comprising the serotonin agonist to the headache region.

In certain embodiments, the present invention further provides forapplying a topical formulation as described herein for the immediaterelease of the serotonin agonist upon an acute attack, plus theapplication of a transdermal therapeutic system (e.g., a patch) for theprophylactic treatment of secondary attacks due to the delayed effect ofthe transdermal therapeutic system.

In certain embodiments, in addition to the serotonin agonist, thetopical formulation or transdermal therapeutic system may furthercomprise another active ingredient in combination with the serotoninagonist, e.g., analgesics, antimimetics, psychopharmacologic agents, orsedatives.

The present invention is contemplated to encompass all transdermalformulations, e.g., the technologies described above, with the inclusionof a serotonin agonist, such that the administration of the serotoninagonist provides for the relief of migraine and/or cluster headaches.

In certain embodiments, the present invention further provides for amethod of manufacturing the formulations of the present inventioncomprising grinding the serotonin agonist (e.g., sumatriptan succinate)into fine particles; mixing the particles with a aqueous and/or organicsolution to provide for a solution or dispersion of the serotoninagonist; filtering and rinsing the residue; preferably bringing thevolume of the filtrate to that of the final product; preferablyconcentrating the filtrate (preferably using a low pressure vacuum) to25% of the original volume; mixing the condensed filtrate with arequisite amount of a carrier (e.g., Lipoderm®); and preferably placingthe final formulation in a metered dosing device (or alternatively,otherwise dividing the formulation into unit doses prior to use).

The present invention will now be more fully described with reference tothe accompanying examples. It should be understood, however, that thefollowing description is illustrative only and should not be taken inany way as a restriction on the generality of the invention specifiedabove.

EXAMPLE 1 Transdermal Gel

A sumatriptan gel was produced with the formula set forth in Table 1below:

TABLE 1 Ingredient Amt/unit (mg) Imitrex ® (sumatriptan succinate) 100mg 2200 mg (22 tablets) tablet Ethoxy Diglycol Liquid 2.200 gmLecithin/Isopropyl Palmitate 50/50 gel 4.400 gm Pluronic F127 20% Liquid11.286 gm

Dosage forms of the above formulation were prepared according to thefollowing procedure:

-   -   1. 100 mg Imitrex® tablets (sumatriptan succinate) are crushed        and mixed with Lecithin/Isopropyl Palmitate 50/50 gel.    -   2. Thereafter, the Ethoxy diglycol liquid is added and mixed        together with 1.    -   3. The pluronic F127 20% is also added to the mixture.    -   4. The resultant formulation is put through an ointment mill and        1 ml unit doses are placed in 1 ml oral syringes. The syringes        contain a gel having a sumatriptan concentration of 100 mg/ml.

EXAMPLE 2 Drug Study Using Formulation of Example 1

An open study was conducted where physician, pharmacist and patient wereaware of the medication being used and aware of the expected results.Two written surveys were sent to each patient and a telephone call wasplaced to those who did not respond to the written survey.

In the study, 43 patients were each given a single 1 ml oral syringecontaining 100 mg/ml of a transdermal sumatripan formulation prepared inaccordance with Example 1. Patients were instructed initially to apply0.25 ml (containing 25 mg sumatriptan) to the temples at the onset ofthe aura of a migraine or at the onset of a migraine (whichever occurredto them). Patients were also told to apply to the base of the neck ifnecessary. Four Band-Aids were dispensed with each prescription and thepatients were told to apply the patch over the transdermal sumatriptan.If a 25 mg dose was not sufficient, the patients were told they couldreapply a second 25 mg dose in 2 hours after the initial dose. Patientswere told to wash their hands after application.

-   -   A. A telephone survey was conducted which gave the following        results:        -   2 of 29 patients preferred injectable sumatriptan;        -   2 of 29 patients preferred nasal sumatriptan;        -   9 of 29 patients were unable to be reached;        -   4 of 29 patients reported transdermal sumatriptan did not            work;        -   6 of 29 patients did not use the transdermal sumatriptan as            of the telephone survey; and        -   6 of 29 patients reported that transdermal sumatriptan            worked well.    -   B. Of the written surveys, fourteen were returned, which gave        the following results:    -   1. With respect to time to pain relief:        -   3 of 14 patients had pain relief within 10 to 15 minutes;        -   3 of 14 patients had pain relief within 30 minutes;        -   2 of 14 patients had pain relief within 60 minutes;        -   1 of 14 patients had pain relief in about 120 minutes;        -   1 of 14 patients had pain relief in longer than 120 minutes;        -   3 of 14 patients did not get relief from transdermal            sumatriptan; and        -   1 of 14 patients did not “really” get relief (however, via            telephone survey, patient said did get relief).    -   2. With respect to recurrence:        -   2 of 14 patients had no reoccurrence;        -   2 of 14 patients had reoccurrence within 1 hour;        -   3 of 14 patients had reoccurrence within 4 hours;        -   1 of 14 patients had reoccurrence within 24 hours;        -   6 of 14 patients did not answer the question; and        -   1 of 14 patients did not get initial relief, therefore            reoccurrence was not applicable.    -   3. With respect to the requirement of a second dose:        -   3 of 14 patients were unable to answer the question;        -   8 of 14 patients did apply a second dose; and        -   3 of 14 patients did not apply a second dose.    -   4. With respect to pain relief if a second dose was applied:        -   4 of 8 patients did not get further pain relief; and        -   4 of 8 patients did not get relief with 50 mg total dose at            that point.    -   5. With respect to whether patients had to use another dosage        form to obtain relief:        -   5 of 14 patients did not have to use any other dosage form            to get relief;        -   3 of 14 patients used nasal as an alternate route;        -   1 of 14 patients used injectable as an alternate route;        -   3 of 14 patients used oral as an alternate route; and        -   2 of 14 patients did not answer the question.

EXAMPLE 3 Drug Study Using Formulation of Example 1

The efficacy of topical sumatriptan was studied over a six-week periodin 22 migraineurs currently treated with injectable, nasal spray or oralsumatriptan. The migraine frequency of the migraineurs for which triptantherapy was used ranged from 1 to greater than 4 per week. Use of thepresently marketed triptan formulations had been established in some ofthe patients for years. The purpose of the study was to determine theeffectiveness and convenience of topical sumatriptan in comparison toprevious formulations.

In the study, 22 patients were each given a single 1 ml oral syringecontaining 100 mg/ml of a transdermal sumatripan formulation prepared inaccordance with Example 1. Patients were instructed initially to apply0.5 ml (containing 50 mg sumatriptan) to the side of the forehead wherethe patient is experiencing their headache at a time that they wouldusually resort to using sumatriptan for relief. The patients were toldthat an additional 0.5 ml (containing 50 mg sumatriptan) could beapplied if the first dose was ineffective, one hour after the initialdose. Application of the topical sumatriptan took about 3 to 5 secondsby placing it on the finger and rubbing the forehead several times.

The following are results of the eleven patients who responded to thesurveys conducted:

-   -   A. 6 out of 11 patients (55%) reported that transdermal        sumatriptan relieved their headache.    -   B. 4 out of 11 patients (36%) reported a preference for the        transdermal route over other routes, giving the following        reasons:        -   1. 3 of the 4 patients indicated because it worked quickly;        -   2. 4 of the 4 patients indicated because it was more            convenient; and        -   3. 3 of the 4 patients indicated because of the lack of side            effects.    -   C. 4 out of 11 patients (36%) achieved relief with a single 50        mg dose and indicated the following times to relief:        -   1. 1 of the 4 patients indicated relief in 10 minutes;        -   2. 1 of the 4 patients indicated relief in 30 minutes;        -   3. 1 of the 4 patients indicated relief in 60 to 120            minutes;        -   4. 1 of the 4 patients did not indicate time to relief.    -   D. The following results were also indicated by the survey:        -   1. 2 of the 11 patients indicated a preference for the            injectable sumatriptan;        -   2. 2 of the 11 patients indicate a preference for the nasal            spray; and none indicated a specific preference for the pill            (oral) form.

EXAMPLE 4 Transdermal Gel

An aqueous based sumatriptan gel was produced with the formula set forthin Table 2 below:

TABLE 2 Ingredient Amt/unit (mg) Imitrex ® (sumatriptan succinate) 100mg 2200 mg (22 tablets) tablet Lipoderm ®/LIP* q.s. *Lipoderm ®/LIP is acommercially marketed compounding agent having the followingingredients: Ethoxydiglycol, Water (Aqua), Glycerin, C₁₂₋₁₅AlkylBenzoate, Glyceryl Stearate, Dimethicone, Cetearyl Alcohol, CetearylGlucoside, Polyacrylamide, Cetyl Alcohol, Magnesium Aluminum Silicate,Xanthan Gum, Aloe Vera (Aloe Barbadensis), Tocopheryl Acetate (Vitamin EAcetate), Prunus Amygadalus Amara (Bitter Almond) Kernel Oil, VitisVinifera (Grape) Seed Extract, Triticum Vulgare (Wheat) Germ Oil,Retinyl Palmitate (Vitamin A Palmitate), Ascorbyl Palmitate (Vitamin CPalmitate), Pro-Lipo Multi-emulsion Liposomic System, Tetrasodium EDTA,Phenoxyethanol, and Sodium Hydroxymethylglycinate.

Dosage forms of the above formulation in Table 2 were prepared accordingto the following procedure:

-   -   1. 100 mg Imitrex® tablets (sumatriptan succinate) are crushed        and mixed with a sufficient amount of Lipoderm® to provide a        sumatriptan concentration of 100 mg/ml.    -   2. The resultant formulation is put through an ointment mill and        1 ml unit doses are placed in 1 ml oral syringes. The syringes        contain a gel having a sumatriptan concentration of 100 mg/ml.

EXAMPLE 5 Drug Study Using Formulation of Example 4

The efficacy of the topical sumatriptan prepared in accordance withExample 4 was studied in 10 migraineurs currently treated withinjectable, nasal spray or oral sumatriptan.

In the study, 10 patients were each given a single 1 ml oral syringecontaining 100 mg/ml of a transdermal sumatripan formulation of Example4. Patients were instructed initially to apply 0.5 ml (containing 50 mgsumatriptan) to the side of the forehead where the patient isexperiencing their headache and 0.5 ml (containing 50 mg sumatriptan)over the posterior cervical area (back-of-the-neck region) on the sameside of the headache at a time that they would usually resort to usingsumatriptan for relief. If the headache was bilaterial, the patientswere instructed to apply one-half of the 100 mg (0.5 ml) to each side ata time that they would usually resort to using sumatriptan for relief.The patients were instructed to “prep” the skin with an alcohol swabprior to the application of the gel to rid the area of dirt, makeup,oil, etc.

The following are results of the ten patients:

-   -   1. There was a greater than 80% headache relief rate as opposed        to the 55% with the oil based formula of example 1.    -   2. There was improved time to headache relief in comparison to        the oil based formula of example 1.    -   3. Relief was apparent in most patients by 10 to 15 minutes, and        complete by 30 to 45 minutes post application.    -   4. The aqueous gel was more easily applied than the oil-based        formula and left little or no residue, which could easily be        wiped away with a wet cloth.    -   5. The initial 100 mg dose was more effective than the previous        50 mg applied in example 3 and was well tolerated and without        significant side effects. There was only an occasional noting of        “a tingling sensation” of the scalp at the site of application.    -   6. The first indication of relief expressed by patients was that        of the frontotemporal scalp and neck muscles “loosening up.”        This was followed by the sensation of “the head feeling lighter”        with eventual relief of throbbing head pain. Similar symptoms        have been expressed by patients habitually using sumatriptan        injection for migraine headaches.

EXAMPLE 6 Drug Study Using Formulation of Example 4

30 established migraineurs were treated with 100 mg of transdermalsumatriptan as prepared in Example 4 for acute moderate-to-severeattacks. Some patients used the transdermal sumatriptan formulation onmultiple occasions. After cleansing with an alcohol swab, thesumatriptan formulation (100 mg/ml) was applied to the posteriorcervical area in close proximity to the brainstem, the site of migrainepathology, i.e., “migraine generator”.

Each patient was requested to answer a questionnaire after using thetopical formulation. With respect to the written questionnaires thepatients responded as follows:

-   -   1. With respect to the symptoms that the patient experienced        during the migraine attack:        -   23 of the patients experienced nausea.        -   9 of the patients experienced vomiting.        -   26 of the patients experienced light sensitivity.        -   16 of the patients experienced sensitivity to sound.        -   18 of the patients experienced neck pain.        -   11 of the patients experienced facial pain.        -   30 of the patients experienced throbbing headache.        -   15 of the patients experienced dizziness/lightheadedness.        -   6 of the patients experienced confusion.

Other: difficulty breathing and shortness of breath (1); syncope (1);insomnia (1); tinnitus (1); anorexia (1); blurred vision (3); sweats(1); cold and clammy (1); neck tightness (3); tightness behind eyes (1);shoulder tightness (1); lethargy (1); sinus pressure (3); scalpsensitivity (1); diarrhea (1); and arm pain (1); sinus congestion (1).

-   -   2. With respect to when the patient first experienced relief of        any migraine symptom(s) (outside of pain relief)*: Total        patients listed is 32 because two of the thirty patients        indicated different times with respect to different occasions of        using the topical formulation.        -   15 first experienced relief in less than 5 minutes.        -   15 first experienced relief in 5 minutes to 15 minutes.        -   2 first experienced relief 16 minutes to 30 minutes.        -   none first experienced relief greater than 30 minutes.    -   3. With respect to when the patient experienced initial relief        of pain*: Total patients listed is 34 because four of the thirty        patients indicated different times with respect to different        occasions of use.        -   7 experienced initial relief of pain in less than 5 minutes.        -   21 experienced initial relief of pain in 5 minutes to 15            minutes.        -   5 experienced initial relief of pain in 16 minutes to 30            minutes.        -   1 experienced initial relief of pain in greater than 30            minutes.    -   4. With respect to when the patient experienced complete pain        relief (pain free)*: Total patients listed is 34 because three        of the thirty patients indicated different times with respect to        different occasions of use (2 patients indicating 2 different        times and 1 patient indicating 3 different times).        -   9 experienced complete pain relief in less than 15 minutes.        -   9 experienced complete pain relief 16 minutes to 30 minutes.        -   6 experienced complete pain relief in 31 minutes to 45            minutes.        -   3 experienced complete pain relief in 46 minutes to 60            minutes.        -   3 experienced complete pain relief in 61 minutes to 90            minutes.        -   3 experienced complete pain relief in 91 minutes to 120            minutes.        -   1 experienced complete pain relief in greater than 120            minutes.    -   5. With respect to when the patient experienced relief of ALL of        the patient's migraine symptoms*: Total patients listed is 32        because two of the thirty patients indicated different times        with respect to different occasions of use        -   5 experienced relief of all migraine symptoms in less than            15 minutes.        -   10 experienced relief of all migraine symptoms in 16 minutes            to 30 minutes.        -   7 experienced relief of all migraine symptoms in 31 minutes            to 45 minutes.        -   3 experienced relief of all migraine symptoms in 46 minutes            to 60 minutes.        -   3 experienced relief of all migraine symptoms in 61 minutes            to 90 minutes.        -   3 experienced relief of all migraine symptoms in 91 minutes            to 120 minutes.        -   1 experienced relief of all migraine symptoms in greater            than 120 minutes.    -   6. With respect to if the patient experienced recurrence of the        headache pain within 24 hours:        -   28 of the patients said that they did not have a recurrence            within 24 hours.        -   2 of the patients said that they did have a recurrence            within 24 hours.    -   7. With respect to whether the patient experienced any side        effects using transdermal sumatriptan:    -   25 of the patients said that they did not experience any side        effects.    -   Of the 5 patients experiencing side effects, side effects listed        were as follows:    -   Tingling and warmth at application site (1); tingling neck and        left hand (1);    -   Tingling of skin at application site (1); burning sensation in        scalp (1); slight tingling of skin and “warm” feeling (1).    -   8. With respect to other forms of migraine medications the        patient has used in the past:        -   30 of the patients said they have used a tablet formulation            to treat migraine.        -   2 of the patients said that they have used a melt            formulation to treat migraine.        -   3 of the patients said that they have used a nasal spray            formulation to treat migraine.        -   9 of the patients said that they have used an injection            formulation to treat migraine.    -   9. Comments that the patient had relative to transdermal        therapy:    -   Comments from the patients varied with respect to the        formulations. Most notably, patients comments were as follows:    -   Cost prohibitive (1); worked better and faster than any other        treatment she used (used tablet and injection in the past) (1);        faster relief (1); worked fast (1); able to use ½ dose        transdermal with success (age 8) (1); never experienced anything        to work so well or so fast (1); on two occasions patient had        taken Imitrex® tablet without benefit, but responded to        transdermal (1); transdermal did not cause lethargy that pill        caused (1); exclusively uses transdermal for migraines; has used        20 times; also 3 week period of headaches stopped only with        transdermal; cream crumbles like any cheese after applied but        “I'm not complaining” (1); regular user of transdermal 10-15        times; transdermal is more subtle than pill (1); has used        transdermal 6-7 times and works faster than pill; application        not convenient and sometimes and pain relief not as long as        imitrex pills (1); faster than pills (1); uses regularly (1);        worked fast, easy to administer (1); very fast without side        effects (1); initial didn't absorb, greasy water based better        (absorbed better); and wonderful (1).    -   10. With respect to whether the patient would use transdermal        sumatriptan again to treat another migraine:    -   All 30 of the patients said they would use transdermal        sumatriptan again to treat another migraine.

Typically the first relief symptom expressed by patients usingtransdermal sumatriptan is the relaxation of cervical musculature,followed by decreased nausea and photophobia and the eventual relief ofthrobbing head pain. It is believed that with the local application oftransdermal sumatriptan, the brainstem and surrounding tissue areconcentrated with the drug accounting for its rapid and prolongedclinical effect. The relative paucity of side effects, particularly thetypical “triptan effects” may be explained on the basis of minimalsystem absorption, with much of the drug remaining concentrated near thesite of application. In view of the above, the data suggests that thetransdermal route is as effective as injection, but without the usualside effects.

As can been seen from the above examples, the percentage of patientsexperiencing migraine or cluster headache pain relief may besignificantly improved using an aqueous based topical formulation.Additionally, the percentage of patients experiencing migraine orcluster headache pain relief may be significantly improved without asignificant increase in side effects using an increased dose asdemonstrated by the above examples.

EXAMPLE 7

A sumatriptan formulation having a final strength of 12.5 mg/0.1 ml wasprepared according to the following procedure:

-   -   1. Triturate the requisite amount of sumatriptan succinate        tablets in a mortar and pestle to a small particle size.    -   2. Wet the powder with 95% ethyl alcohol and triturate. Add pure        water and triturate again.    -   3. Filter and rinse the residue twice with enough water to bring        the volume of the filtrate to that of the final product. For        example, if preparing 100 ml of the transdermal migraine        formulation, filter until the total volume of the filtrate        reaches 100 ml.    -   4. Concentrate the filtrate using low pressure vacuum to 25% of        the original volume (e.g., to 25 ml in the example).    -   5. Mix the condensed filtrate and Lipoderm® in mixing syringes        to the desired volume (e.g., 100 ml in step 3). The final        strength is 12.5 mg of sumatriptan succinate per 0.1 ml.

EXAMPLE 8

12 migraineurs (patient 8 was treated on two occasions) were eachtreated with 12.5 mg of sumatriptan of the formulation prepared inaccordance with Example 7. The patients were told to clean the back ofthe neck with an alcohol swab and dry with a clean tissue beforeapplication. The patients were told withdraw 12.5 mg (0.1 ml) of thetransdermal sumatriptan gel contained in a calibrated 1 ml syringe formetered administration, and apply 12.5 mg of the transdermal sumatriptangel by gently rubbing the gel into the skin on the back of the neck atthe onset of headache and repeating in one-half hour if migrainepersists. The following table lists the results.

TABLE 4 Initial relief of headache and migraine Complete Age in Yearswith symptoms pain relief Patient # years Sex migraine (minutes)(minutes)  1 50 F >20 1 10  2 42 F 16 2-3 10-12  3 47 F 20 3 25 (12.5 mgreapplied after recurrence with subsequent complete relief)  4 45 F 11 215-20  5 52 F >30 3-5 15  6 37 F 11 2 15-20  7 17 F 1 3-5 20-25  8(a) 17F 1½ 1  8  8(b) 2 20  9 36 F 20 2 30 10 37 F 23 3 15 11 66 F 2 yearswith 2 15 muscle contraction headaches 12 55 F 8 years with  8-10 30-45muscle contraction headaches after auto accident

Many other variations of the present invention will be apparent to thoseskilled in the art and are meant to be within the scope of the claimsappended hereto.

1. A method for treating a migraine or cluster headache comprising:applying a topical formulation containing an effective amount ofsumatriptan or a pharmaceutically acceptable salt thereof topically tothe skin at the posterior cervical area of a human patient in closeproximity to the brain stem, the topical formulation comprising thesumatriptan in an immediate release topical vehicle and providing rapiddelivery of the sumatriptan for immediate absorption at the posteriorcervical area of the human patient, to provide relief of a migraine orcluster headache which is occurring or is imminent in the patient. 2.The method of claim 1, further comprising preparing the topicalformulation as a preparation selected from the group consisting of acream, gel, lotion, emulsion, viscous liquid, and foam.
 3. The method ofclaim 2, further comprising preparing the topical formulation in anaqueous based vehicle.
 4. The method of claim 3, wherein saidsumatriptan is in a topical formulation selected from the groupconsisting of a cream, gel, lotion, emulsion, viscous liquid, and foam.5. The method of claim 1, wherein the patient experiences relief of themigraine or cluster headache within about 2 hours after applying thetopical formulation.
 6. The method of claim 1, wherein said amount ofsaid sumatriptan is in an amount of from about 0.5 mg to about 200 mg.7. The method of claim 1, wherein a unit dose of the topical formulationcontaining sumatriptan or a pharmaceutically acceptable salt thereofcomprises from about 0.5 to about 200 mg of sumatriptan, by weight basedon the succinate salt of sumatriptan, said unit dose providing relieffrom a migraine or cluster headache within about 2 hours after topicaladministration to said human patient.
 8. The method of claim 1, furthercomprising applying a second application of said sumatriptan to the sameor different headache region within about 2 hours after applying thefirst application.
 9. The method of claim 1, further comprising applyingthe formulation to an area of intact skin in the range of about 20 cm²to about 60 cm².
 10. The method of claim 1, further comprising reducingthe side effects of said sumatriptan as compared to oral administrationof said sumatriptan by applying the formulation to the posteriorcervical area.
 11. A method for treating a migraine or cluster headachecomprising: applying a dose of a topical formulation containing aneffective amount of sumatriptan or a pharmaceutically acceptable saltthereof topically to the skin at the posterior cervical area of a humanpatient in close proximity to the brain stem, the topical formulationcomprising the sumatriptan in an aqueous based immediate release topicalvehicle and providing rapid delivery of the sumatriptan for immediateabsorption at the posterior cervical area of the human patient, toprovide relief of a migraine or cluster headache which is occurring oris imminent in said patient, the dose of the sumatriptan comprising fromabout 0.5 to about 200 mg of sumatriptan, by weight based on thesuccinate salt of sumatriptan, wherein the dose provides relief from amigraine or cluster headache within about 2 hours after topicaladministration to the human patient.
 12. The method of claim 11, whereinsaid sumatriptan is in a topical formulation selected from the groupconsisting of cream, gel, lotion, emulsion, viscous liquid, and foam.13. The method of claim 11, further comprising reducing the side effectsof the sumatriptan as compared to oral administration of the sumatriptanby applying the formulation to the posterior cervical area.
 14. Themethod of claim 11, further comprising providing the dose of thesumatriptan in a metered dose device containing multiple unit doses ofthe sumatriptan.
 15. The method of claim 11, wherein the sumatriptan isselected from the group consisting of sumatriptan base, sumatriptansuccinate, and mixtures thereof.
 16. The method of claim 11, wherein thepatient experiences pain relief within less than about 30 minutes afterapplication of the dose.
 17. A method for treating a migraine or clusterheadache comprising: topically applying a dose of a topical aqueousbased immediate release formulation containing from about 0.5 to about200 mg of sumatriptan, by weight based on the succinate salt ofsumatriptan, to the skin at the posterior cervical area of a humanpatient in close proximity to the brain stem, to provide rapid deliveryof the sumatriptan for immediate absorption at the posterior cervicalarea of the human patient such that the dose provides relief from amigraine or cluster headache within about 2 hours after topicaladministration to the human patient, the topical formulation selectedfrom the group consisting of cream, gel, lotion, emulsion, viscousliquid, and foam.